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Themes in Literature Related to Incidence, Risk, and Prevention of Cancer in Solid-Organ Transplantation Recipients on Immunosuppressive Therapy

Rashti, Stefanie L., MSN, MEd, RN-BC, PCCN

doi: 10.1097/NCC.0000000000000558
ARTICLES: ONLINE ONLY
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Background Solid-organ transplants provide a second chance to thousands of critically ill patients with end-organ failure each year. Immunosuppressants are administered to patients to prevent graft rejection of a transplanted organ, such as a heart, kidney, or liver, while placing the recipient at greater risk for infection and cancer.

Objective The literature provides evidence of various cancers that have been found to develop in patients’ posttransplantation. The purpose of this comprehensive review is to investigate the incidence, risk, and prevention of cancer in solid-organ transplantation recipients on immunosuppressive therapy.

Methods Google Scholar, Cumulative Index to Nursing and Allied Health Literature and Ovid databases were searched to identify research articles in peer-reviewed journals from 2011 to 2016. Variables under examination included cancer risk, cancer type, incidence, demographic characteristics, prevention, screening modalities, and education tools.

Results Six articles met the inclusion criteria. Results indicate that malignancy is a prominent postoperative finding in at least 4% to 5% of solid-organ transplant recipients, with evidence of various cancer types. Risk factors include male sex, increased age, number of years posttransplant, fair skin, white race, and UV exposure. Screening intervals and educational tools have been found to increase awareness and target those at greater risk.

Conclusion Skin cancer and non-Hodgkin lymphoma were the most commonly diagnosed cancers in transplant recipients.

Implications for Practice Practitioners may find utility in screening tools, self-examination education for patients, and follow-up protocols to prevent further complications in this patient population. Early detection of cancer and those at risk may help decrease morbidity and mortality rates in organ recipients.

Author Affiliation: Graduate School of Nursing, Thomas Jefferson University, 8th Floor, Philadelphia, PA.

The author has no funding or conflicts of interest to disclose.

Correspondence: Stefanie L. Rashti, MSN, MEd, RN-BC, PCCN, Graduate School of Nursing, Thomas Jefferson University, 8th Floor, Health Professions Academic Bldg, 901 Walnut St, Philadelphia, PA 19107 (stefanie.rashti@jefferson.edu).

Accepted for publication May 3, 2017.

According to the United Network for Organ Sharing, almost 25 000 total transplants were performed in 2016.1 Solid-organ transplants provide a second chance to thousands of critically ill patients with end-stage organ failure each year. Although drastically improved outcomes have been achieved since the first human kidney was transplanted in 1954,1 recipients are faced with the potential for acute rejection of the graft, risk of infection, and development of various malignancies. To prevent graft rejection, immunosuppressive therapy agents are prescribed for the remainder of the recipient’s life. These agents aid in preventing rejection by suppressing the immune system, decreasing the body’s ability to reject a transplanted organ, such as a heart, kidney, liver, or lung. Immunosuppressants weaken the immune system, putting a patient at risk for opportunistic infections and decreased cancer surveillance. Chronic exposure to immunosuppressive agents has been shown to increase risk of cancer and has become a significant cause of morbidity and mortality in patients with solid-organ transplants.2 The literature provides evidence of various malignancies that have been found to develop in patients’ posttransplantation. This comprehensive review will highlight the incidence, risk, and prevention modalities of cancer in solid-organ transplant recipients on immunosuppressive therapy.

Maintenance immunosuppressive therapy is administered to organ-transplant recipients to prevent loss of the allograft and prevent acute rejection.3 Various combination medication regimens include glucocorticoids such as oral Prednisone, an antimetabolite, such as azathioprine or mycophenolate mofetil, and a calcineurin inhibitor, such as tacrolimus or cyclosporine. Within the first 3 months of transplantation, a stable medication regimen is established. For those patients who develop posttransplant complications such as toxicity, allograft failure, infection, cancer, or acute rejection, medications must be adjusted or reduced.3 An increased incidence of opportunistic infections occurs in patients in the postoperative period because of immunosuppression, and patients are often administered prophylactic medications to prevent or treat an infection. Most patients receive oral trimethoprim-sulfamethoxazole; influenza, pneumococcal, and hepatitis B vaccines; and anti-CMV prophylaxis such as valacyclovir.4

The risk of developing cancer after transplantation is multifactorial.

There are numerous potential mechanisms secondary to long-term immunosuppression that may increase the risk of cancer development.

These mechanisms include the increased risk of oncoviral-driven malignancy, reduced immune surveillance of neoplastic cells, and the possibility of some agents containing pro-oncogenic properties.2 Because cancer is a major cause of morbidity and mortality in patients after solid-organ transplant, it is vital for clinicians to identify the risks and incidence of common cancers in this population to provide better screening measures for practitioners in the postoperative management period.

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Methods

Search Strategy

Google Scholar, Cumulative Index to Nursing and Allied Health Literature, and Ovid databases were searched, and the literature was identified within a 5-year period (2011-2016). The articles reported data collected ranging from 1970 to 2009. The literature search was followed by a hand reference list reviewing for relevant articles from these 3 databases. Subject heading terms used in Google Scholar were cancer, organ transplant, and immunosuppressive therapy. Subject heading terminology used in Cumulative Index to Nursing and Allied Health Literature and Ovid search were cancer risk and solid-organ transplant.

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Inclusion Criteria

The sources reviewed were research articles published in peer-reviewed journals within the specified 5-year period. The studies were peer reviewed and were relevant to cancer and solid-organ transplant in patients on immunosuppressive therapy. They included one or more of the variables associated with cancer and organ transplant such as population demographics (age, sex, type, and site of cancer), risk factors, incidence of cancer, screening modalities, and prevention measures. Data extraction and key findings from the literature were organized into a summary table. The table catalogs articles alphabetically by author including citation, sample, method, findings and study limitations (see Table).

Table

Table

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Results

Cancer Type, Incidence, and Risk Factors

Swedish researchers performed a retrospective study evaluating the overall cancer risk of solid-organ transplant recipients in Sweden from 1970 to 2008.5 Researchers excluded patients with cancer in situ, those with basal cell carcinoma (BCC), patients with a history of cancer before transplantation, and those diagnosed within 30 days of first transplantation. The study surveyed a large sample size of recipients over a 30-year period. Researchers investigated overall cancer risks, risks by transplanted organ, and risk by follow-up time. After 801 patients were excluded from further analysis due to exclusion criteria, a final cohort of 10 476 patients were further evaluated. During follow-up, 1610 transplanted patients developed 3406 malignancies. Study results indicated that the risk of cutaneous squamous cell carcinoma (SCC) had superseded all other cancer risks, with the highest incidence observed in heart and lung recipients.5 The risk of SCC was 198-fold for heart and/or lung recipients and 121-fold in liver and kidney recipients.5 Very rare skin cancer types were also observed such as Merkel cell carcinoma, Kaposi’s sarcoma, and appendageal carcinoma, although in only a small population of recipients.

An increased risk of oral cancer in kidney, heart, and/or lung recipients was found, as well as cervical cancer in kidney recipients, with a suggestive association of human papillomavirus (HPV) infection. Transplant recipients are more susceptible to viral infection or recurrence of a latent viral infection because of immunosuppressive activity that can stimulate unbridled viral replication.6 Viruses associated with carcinogenesis include non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma that have both been linked to Epstein-Barr virus, HPV, Kaposi’s sarcoma (human herpes virus 8), Merkel cell polyomavirus, and hepatitis B and C.6,7

Further results of Krynitz and colleagues’5 study indicated that the risk of developing cancer increased with number of years posttransplant and that there is a 50-fold increased rate of mortality in transplanted patients with SCC on immunosuppressive therapy in comparison with the general population. It is believed by researchers that this accelerated and augmented rate of skin carcinogenesis is complex and may be due to the combination of genetic components, UV light and HPV exposure, and age.5 Krynitz and colleagues5 encourage regular skin screening, posttransplant routine visits and cancer screening checklists due to the elevated risk of cancer at a range of sites, with the most discernable risk for SCC.

The Scientific Registry of Transplant Recipients (1987-2008) links data with the Transplant Center Match Study from 14 US state/regional cancer registries. A retrospective study, by Hall and colleagues,8 investigated the cumulative incidence and risk of cancer after solid-organ transplantation in 164 156 recipients using data from the aforementioned registries. From this large population, 8520 cancers were identified. Data analyses reported an increased risk of cancer for recipients of male sex and those of increasing age (>60 years). Lung recipients had the highest cumulative incidence of cancer. Nonmelanoma and NHL were the most common cancers identified in posttransplant recipients. Poor immune control of Epstein-Barr virus has been connected to the high incidence of NHL and posttransplant lymphoproliferative disease (PTLD).6,8

Hall and colleagues8 reported that heart and lung recipients older than 50 years were at greatest risk of developing NHL. The most common form of cancer in kidney recipients was kidney cancer and was often found in native kidneys in association with polycystic kidney disease. The incidence of colorectal cancer was also high in the older recipient population (ages >50 years). Researchers note that improvements in clinical management may have provided an increased opportunity for cancer development because recipients are living longer with functioning grafts.8 This study demonstrated evidence of the most commonly found cancers after transplantation, including incidences and risk factors of NHL, lung, kidney, prostate, breast, colorectal, and skin cancer and the significance of screening for each of these cancers.

Several researchers have investigated the incidence of posttransplant malignancies in the United States. An analysis performed by Sampaio and colleagues9 reviewed the US National Transplant database for solid-organ transplants performed between 1999 and 2008. The database included information on 193 905 transplants (123 380 kidney, 43 106 liver, 16 511 heart, and 10 908 lung).9 Risk factors for posttransplant malignancies among all organ types included increased age (>39 years), male sex, and white race. In kidney and liver recipients, the most prevalent cancer types were PTLD and lung cancer.

In heart recipients, lung cancer and prostate cancers had the highest incidence. Heart recipients defined as HBV-positive status were also associated with increased risk. In lung recipients, the highest incidence of cancer types were lung and bronchial cancer, with risk factors including age (>50 years), male sex, and HCV-positive status. Researchers believe that the higher incidence in thoracic organ recipients compared with abdominal organ transplant recipients is because of the more intense immunosuppression prescribed in thoracic organ transplant patients. Lung, bronchial, and Kaposi’s sarcoma and PTLD were increased among all types of solid-organ transplant recipients reviewed in the database. Researchers note that the intensive surveillance of transplant recipients may increase findings and cancer incidence because they are clinically and radiologically examined more frequently than the general population.9 They also report the limitations of possible underreported cancer occurrences to United Network for Organ Sharing because of factors that may compete such as loss of follow-up, graft loss, or rejection, and death.9

Mudigonda and colleagues10 examined the results of more than 30 retrospective single-center and multicenter studies that reported skin cancer incidence between 2006 and 2010. This comprehensive review examined data focusing on skin cancers as opposed to other known cancer types found in organ-transplant recipients. Researchers thoroughly examined the incidence and risk factors of various skin malignancies, the pharmacology of most commonly used immunosuppressants, sex and age at transplantation, skin type, and several risk factor categories. The study also included preventative management measures.

Nonmelanoma skin cancer (NMSC), which included SCC and basal cell carcinoma, was the most common cutaneous malignancy found in organ-transplant recipients.10 The mean age to diagnosis for a first NMSC occurrence was reported between 4 and 9 years posttransplant, with the primary lesion occurring on the head and neck as well as other sun-exposed areas. Risk factors for malignancy included male sex, longer posttransplantation follow-up time, older age, fair skin, increased sunlight exposure, and living in the northern hemisphere.

Additional risk factors for NMSC include premalignant infections with HPV and posttransplant viral warts in recipients on chronic immunosuppressive medications.10 Human papillomavirus is believed to infect the squamous epithelium of the skin, with increased activity in an immunosuppressed patient.10 The earliest identifiable premalignant lesions that can advance into invasive SCC are actinic keratoses.10 Actinic keratosis was found in 50% of organ-transplant recipients and was associated with older age and male sex. Although a rare vascular tumor affecting the visceral organs and skin, organ-transplant recipients are 20 times more likely to acquire Kaposi’s sarcoma than the nonimmunosuppressed population.10 Greater incidences of Kaposi’s sarcoma were found in Middle Eastern recipients, patients who were older than 30 years at transplantation, and patients with particular immunosuppressive therapy regimens including cyclosporine, azathioprine, and prednisolone.10 Incidence of melanoma and Merkel cell carcinoma were also evaluated and, although both are rare, were found in less than or equal to 1% to 2% of transplant recipients.10

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Cancer Screening

A specialist skin cancer surveillance clinic was started in London in 1989 where all kidney transplant recipients were referred and seen within 6 to 12 months of transplantation.11 Harwood and colleagues11 investigated the overall burden of cancer and appropriate time intervals for strategic surveillance, in a cohort of 1010 transplant recipients in a UK center, over a 22-year period. Referred by their transplant clinician, all transplant recipients were scheduled to follow-up for a full-skin examination at least annually in patients with no evidence of skin cancer and at least every 3 to 4 months in those with skin cancer. A total of 267 of the 931 patients included in the study developed skin cancer. Risk factors of skin cancer include older age at transplant, skin phototype in white Europeans, pretransplant sunburn, high ultraviolet radiation exposure, and male sex.11 Results indicated that mean time from transplant to first skin cancer was 8.8 years and risk of second and subsequent cancers is high after diagnosis of a first skin cancer.

Although rare, researchers discovered 20 cases of metastatic disease and 15 recipients who were diagnosed with Kaposi’s sarcoma.11 Researchers noted a 150-fold increased risk for developing SCC and dying from it in transplant recipient patients. The surveillance model used by researchers in this study was chosen to allow closer follow-up for at-risk patients while preventing the burdensome evaluation of those at lower risk. Harwood and colleagues11 noted that only patients in the highest risk group required annual screenings and, for those at lower-to-medium risk, surveillance can decrease to 2 to 5 years.

An educational intervention was developed for kidney transplant recipients to detect SCC, by promoting skin-self examination techniques.12 Seventy-five kidney transplant recipients returned to their nephrologist for routine care, in intervals of either 1–1.2 years or 3–7 years post-transplant. The educational materials consisted of a pneumonic and workbook, including clinical features associated with SCC, and what to do if the patient found a concerning lesion. The study measured self-skin examination performance and if the patient made a subsequent appointment with a dermatologist after finding a questionable mole or lesion. Study results indicated that prior to the intervention, recipients did not likely examine certain areas of the body or face. The 3–7 year post-transplant group found greater areas of concern than the 1–2 year group, indicating that the likelihood of finding a precancerous or cancerous lesion increases with number of years post-transplantation. Researchers found that the frequency of patient visits in the first year post-transplant gave practitioners and nephrologists the greatest opportunity to assess, provide education, and counseling.12

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Discussion

Organ-transplant recipients are placed on a stringent post-operative assessment and medication regimen in order to decrease morbidity and mortality. Immunosuppressive agents and graft survival have improved over the past few decades however the main obstacles after transplant include malignancy and infection. The risk of developing cancer has been shown to increase with number of years post-transplant, as well as a 50-fold increased rate of mortality in transplanted patients on immunosuppressive therapy in comparison to the general population. Studies have identified those at highest risk for developing skin cancer which include older age at transplant, skin phototype in white Europeans, pre-transplant sunburn, high UVR exposure and male sex.9–11

Because cutaneous squamous cell cancers are one of the most frequently researched and diagnosed cancers after transplant, dermatological management is crucial in the recipient’s care plan.7 Several studies report the importance of rigorous sun protection, including protective clothing and regular sunscreen application, early detection of skin lesions, sun protection programs, and self-skin examination education, most importantly in the high-risk groups as noted earlier.8,10,12 Annual dermatologist inspections are imperative for all patients in the posttransplant period.6 Scheduled surveillance intervals should be developed for suspicious or precursor skin lesions.7,11,12

Data have shown that NHL is also one of the most commonly diagnosed malignancies in transplant recipients.7 There are no widely recommended screening tests for lymphoma or NHL.13 Most patients visit their physician after noticing an enlarged lymph node that has not disappeared for a period of time. Enlarged lymph nodes are often the result of infection, so many physicians will rule out common infections before linking the diagnosis to lymphoma. Several diagnostic studies may be performed including biopsy, immunohistochemistry tests, blood tests, lumbar puncture, and various imaging tests.13 It is important for providers to educate patients regarding the signs and symptoms of NHL, the common areas of enlarged lymph node findings (such as the neck, groin, axilla, and clavicle), self-examination techniques, and following up with scheduled appointments for regular blood tests and physical examinations with their transplant physician.

Screening measures for cervical cancer are indicated for female recipients because of overall incidence increasing 2- to 3-fold after transplantation.6 Annual cytological screenings are recommended because of the possibility of precancerous lesions rapidly progressing due to immunosuppressive therapy agents.6 Studies have not indicated the need for HPV vaccinations in this study group because of increased cost and no evidence of benefit. Studies have reported no elevated risk of prostate or breast cancer in posttransplant recipients.6,8 Lack of data and uncertainties in the specificity and sensitivity of screening tests such as mammography, digital rectal examination, and serum prostate-specific antigen in the transplant setting deem these screenings unwarranted for the transplant population as a whole.6,8

Studies have also discussed the need for routine colorectal, lung, and kidney cancer screenings in the general posttransplant recipient population. Standard colorectal cancer screenings should begin at age 50 years. Further screenings for colorectal, lung, and kidney cancer may only be cost effective in high-risk patients with polycystic kidney disease, family history of cancer, specific genetic syndromes, and tobacco use.8

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IMPLICATION FOR FUTURE RESEARCH

Researchers believe that there may be benefits to modifying immunosuppressive regimens; however, adjusting medications may create a greater risk of allograft rejection and infection.10 Studies have evaluated the overall cancer risk by the intensity and duration of immunosuppressive medications.6,10 Some suggest lowering the level of immunosuppression to decrease risk and incidence of cancer; however, studies have failed to show association of overall cancer risk with any specific medication.6,10 Further research is needed to assess the efficacy of modification and reduction of immunosuppressive drug regimens, which may concurrently prevent cancer while allowing for best graft function.

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IMPLICATIONS FOR HEALTHCARE PRACTICE

Healthcare providers should place a major emphasis on educating patients regarding the risks of cancer in the postoperative period and screening measures to identify the most common malignancies. Providing education and screening tools for all patients in the postoperative period ensures an extension of the providers’ knowledge into the hands of the patients.

Successful organ transplantation requires all members of the healthcare team to work together to provide bedside care, education, physical and psychosocial support, and continued follow-up examinations. Educating nurses, midlevel practitioners, and physicians on the latest research and innovations in the field of transplantation is vital in promoting the best perioperative and postoperative care for this patient population. Cancer screening surveillance should be adapted as a standard practice for health policies in clinics and hospitals that care for organ-transplant recipients. Dermatological inspections, sun protection programs, and self-screening tools should be implemented for all patients in the posttransplant period.8

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Conclusion

Several studies have researched the incidence, risk, and screening modalities of cancer in the organ-transplant recipient population, as well as the effects of immunosuppressive medications and the increased risk for infection in the postoperative period.5,8,11 Continued studies of recommended cancer screening intervals and preventative practice will help to protect our organ-transplant population from further complications and improve their quality of life.

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References

1. United Network for Organ Sharing. Transplantation. United Network for Organ Sharing Web site. https://www.unos.org/transplantation/. Accessed November 13, 2016.
2. Sherston SN, Carroll RP, Harden PN, Wood KJ. Predictors of cancer risk in the long-term solid-organ transplant recipient. Transplantation. 2014;97(6):605–611.
3. Hardinger K, Brennan DC. Maintenance immunosuppressive therapy in renal transplantation in adults. UpToDate Web site. https://www.uptodate.com/contents/maintenance-immunosuppressive-therapy-in-renal-transplantation-in-adults?source=search_result&search=organ%20transplant%20immunosuppress&selectedTitle=1~150. Accessed February 28, 2017.
4. Alexander BD, Fishman JA. Prophylaxis of infections in solid organ transplantation. UpToDate Web site. https://www.uptodate.com/contents/prophylaxis-of-infections-in-solid-organ-transplantation?source=see_link#H3072141262. Accessed February 28, 2017.
5. Krynitz B, Edgren G, Lindelöf B, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008—a Swedish population-based study. Int J Cancer. 2012;132(6):1429–1438.
6. Chapman JR, Webster AC, Wong G. Cancer in the transplant recipient. Cold Spring Harb Perspect Med. 2013;3:1–7.
7. Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891.
8. Hall EC, Pfeiffer RM, Segev DL, Engels EA. Cumulative incidence of cancer after solid organ transplantation. Cancer. 2013;119(12):2300–2308.
9. Sampaio MS, Cho YW, Qazi Y, Bunnapradist S, Hutchinson IV, Shah T. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. Transplantation. 2012;94(10):990–998.
10. Mudigonda T, Levender MM, O’Neill JL, West CE, Pearce DJ, Feldman SR. Incidence, risk factors, and preventative management of skin cancers in organ transplant recipients: a review of single- and multicenter retrospective studies from 2006 to 2010. Dermatol Surg. 2013;39(3Pt1):345–364.
11. Harwood CA, Mesher D, McGregor JM, et al. A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population. Am J Transplant. 2013;13(1):119–129.
12. Robinson JK, Turrisi R, Mallett KA, et al. Efficacy of an educational intervention with kidney transplant recipients to promote skin self-examination for squamous cell carcinoma detection. Arch Dermatol. 2011;147(6):689–695.
13. Society AC. American cancer society. http://www.cancer.org/cancer/non-hodgkinlymphoma/index. Accessed November 23, 2016.
Keywords:

Cancer; Cancer prevention; Cancer risk; Cancer screening; Immunosuppression; Solid-organ transplant

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